Dipeptidyl peptidase IV (DPPIV) inhibitors are a new class of drugs for treatment of type 2 diabetes. Because drugs in this class [e.g., sitagliptin (Januvia)] afford sustained reductions in HbA1c with a low risk of hypoglycemia and little effect on body weight, it is likely that DPPIV inhibitors will be extensively employed to manage the world-wide pandemic of type 2 diabetes and the metabolic syndrome. Indeed, sitagliptin is already the 2nd leading branded oral antidiabetic agent in the USA. In the near future, tens of millions of patients will be taking DPPIV inhibitors, many for the rest of their lives; thus, we should strive to fully understand the risks, both short-term and long-term, associated with DPPIV inhibition. Based on their mechanism of action, we anticipate that DPPIV inhibitors will express adverse effects. DPPIV metabolizes incretin hormones [e.g., glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP)], and consequently DPPIV inhibitors raise circulating levels of incretins and thereby exert antidiabetic actions by increasing insulin release, inhibiting glucagon secretion and retarding gastric emptying. However, DPPIV metabolizes at least 35 endogenous substrates, and the pharmacological consequences of inhibiting the metabolism of these substrates are mostly unknown. Of particular concern to us is the fact that DPPIV converts neuropeptide Y1-36 (NPY1-36) and peptide YY1-36 (PYY1-36), which is Y1 receptor (Y1R) agonists, to NPY3-36 and PYY3-36, respectively, which are selective Y2 receptor (Y2R) agonists. Indeed, DPPIV could just as logically be named NPY Converting Enzyme because the kcat/Km of DPPIV for NPY1-36 is approximately 36-fold and 73-fold greater for NPY1-36 compared with GLP-1 and GIP, respectively. Clearly DPPIV inhibitors may alter the balance between Y1R and Y2R stimulation, and this may have adverse renal consequences. For example, our previously published work shows that DPPIV inhibition augments angiotensin II-induced renal vasoconstriction in genetically-susceptible kidneys via a Y1R mediated action. Moreover, our recently obtained pilot data suggest that NPY1-36 and PYY1-36 stimulate (via Y1R activation) proliferation of, and extracellular matrix production by, preglomerular vascular smooth muscle cells (PGVSMCs) and glomerular mesangial cells (GMCs) obtained from genetically-susceptible kidneys and that inhibition of DPPIV augments these effects. Our pilot data also suggest that the scaffold protein RACK1 is responsible for the greater effects of Y1R activation and DPPIV inhibition in PGVSMCs and GMCs from genetically-susceptible kidneys. These preliminary findings motivate us to test the following hypothesis: Inhibition of DPPIV in PGVSMCs and GMCs prevents the local metabolism of NPY1-36 and PYY1-36, thus increasing Y1R activation in PGVSMCs and GMCs. In PGVSMCs and GMCs from kidneys that are genetically-susceptible, this mechanism leads to RACK1 mediated enhancement of cellular proliferation and extracellular matrix production, thus increasing the risk of glomerulosclerosis and renal dysfunction. PUBLIC HEALTH RELEVANCE: Inhibitors of DPPIV represent a novel class of antidiabetic drugs for treatment of Type 2 diabetes, and drugs in this class, for example sitagliptin (Januvia(R); recently FDA approved), afford significant and sustained reductions in HbA1c with a low risk of hypoglycemia and little effect on body weight. These characteristics of DPPIV inhibitors, along with the emerging uncertainty regarding the safety of thiazolidinediones, make it highly likely that DPPIV inhibitors will be extensively employed to manage the world-wide pandemic of type 2 diabetes; indeed, the DPPIV inhibitor sitagliptin is the 2nd leading branded oral antidiabetic agent in the USA. Because in the near future >100 million patients yearly will be taking DPPIV inhibitors and because patients who are prescribed DPPIV inhibitors will continue to consume them for the remainder of their lives, there is some urgency to more fully understand the long-term risks associated with DPPIV inhibition. The long-term risks of DPPIV inhibitors in the setting of hypertension and the metabolic syndrome are of particular concern because frequently these conditions are co-morbidities in type 2 diabetics. The present proposal examines the critical issue as to whether inhibition of renal DPPIV has adverse effects on the kidneys of animals with hypertension, with and without the metabolic syndrome that could accelerate the development of diabetic renal disease.